THE SISTER STUDY We will study environmental and genetic risk factors for breast cancer in a cohort of 50,000 sisters of women who have had breast cancer. In the United States, there were approximately 192,000 new cases of breast cancer in 2001, with more than 200,000 cases expected in 2002. Breast cancer accounts for over 30% of all new cancer cases among women and 15% of cancer deaths. The etiology of breast cancer is complex, with both genetic and environmental factors playing a role. By focusing on a genetically susceptible group, more precise estimates of the contribution of environmental and other non-genetic factors to disease risk may be possible. The cohort will be followed actively for the development of breast cancer and other diseases. We expect, on average, 300 new cases of breast cancer to be diagnosed each year in a cohort of 50,000 sisters aged 35-74 years. Thus, after five years of follow-up, we will have sufficient power, with about 1,500 new breast cancer cases, to address many key hypotheses regarding gene-environment interactions. Baseline questionnaires, banked blood, urine, and toenail samples, as well as banked environmental samples will provide a rich resource for testing current and future hypotheses regarding breast cancer risk. Follow-up questionnaires will update exposure and medical histories as well as provide an opportunity to collect new data and environmental samples to evaluate emerging hypotheses. Nested case-control or case-cohort analyses will be carried out among sisters who develop cancer and a sample of those who do not, to assess specific gene-environment interactions. Once assembled, the cohort also will provide the structure for assessing gene-environment interactions in risk for other diseases and will provide opportunities for add-on studies. THE TWO-SISTER STUDY We also will enroll 1,600 sisters recently diagnosed with breast cancer, who were under 50 when diagnosed, and whose sister is a Sister Study participant. We will collect DNA from the affected sister and from their parents, creating a nuclear family foursome or tetrad. This novel design will enable powerful analyses of joint effects of genes and environmental factors in young-onset breast cancer.